Background: Classical Osteogenesis Imperfecta (OI) is caused by primary defects in type I collagen, the major protein of the extracellular matrix of bone and skin. Each molecule of type I collagen is composed of three chains, two copies of the a1(I) chain and one copy of the a2(I) chain. The two alpha chains are similar to each other but they are not identical; each alpha chain is coded by a separate gene, COL1A1 and COL1A2, respectively. Furthermore, each person has two copies of COL1A1 and COL1A2, since they inherit one copy of each gene from their mother and another copy from their father.

Classical OI has a dominant inheritance pattern. This means that a mutation (genetic change) in one of the two copies of either COL1A1 or COL1A2 will cause symptoms of OI.

Mild OI (Sillence Type I OI) is caused by quantitative defects in type I collagen (1). These individuals synthesize only normal collagen but in about half the normal amount. Usually these individuals have a mutation in one COL1A1 gene copy that leads to decreased or absent production of collagen alpha chains.

The greater clinical symptoms of Sillence types II, III and IV are caused by structural changes in type I collagen. The OI Mutation Consortium, an international collaboration of many laboratories that identify OI mutations, has found that 80% of mutations result in substitutions for glycine residues in either type I collagen chain, while 20% of mutations cause abnormalities of splicing, the process that puts together the final mRNA coding sequence for a collagen chain (2).

Parental Status: Most collagen mutations occur de novo, that is, they are new mutations that occur in one sperm or one egg as a random event and the couple has no increase in their risk of having a second child with OI. However, a small proportion of couples (< 10%) who have had one child with OI are at increased risk of having a second child with OI because one partner is a mosaic carrier. Mosaic carriers have the collagen mutation in some cells of their body but not in others (hence, the term "mosaic"). The collagen mutation occurs during the fetal development of the mosaic carrier and all cells that arise from the first cell with a mutation will also carry the mutation. This includes germ cells (eggs or sperm) and some body cells. The mosaic carrier does not have symptoms of OI or may have very mild symptoms (blue sclerae, shorter stature, dentinogenesis imperfecta).

In the BEMB, NIH, we always encourage parents of affected individuals to have testing for mosaicism status once the primary mutation has been identified. Usually testing for mosaicism can be done on DNA from a blood sample. If a parent is identified as a mosaic carrier, we offer bone density testing to the carrier; we also offer individual counseling by telephone or in person so that the mosaic carrier and their partner understand their recurrence risks.

Biochemical Test: This is a gel electrophoresis test of the collagen synthesized by cultured skin cells. Specifically, investigators are looking for evidence that the folding of the collagen is abnormal, resulting in “overmodification" of collagen by the enzymes that modify the collagen chains during helix assembly and folding, prolyl 4-hydroxylase and lysyl hydroxylase and associated glycosylating enzymes. This is an excellent test of collagen function. It does not identify the specific mutation. Mutations located in the amino-terminal region of the collagen chains may be missed by this test and require supplementation by molecular testing for detection.

Molecular Test: The goal of this test is identification of the specific mutation in the affected individual. Molecular testing may involve sequencing of DNA extracted from blood cells. It may also be conducted as sequencing of the coding regions of the type I collagen mRNA from skin cells.

Samples Needed: The initial testing generally involves a skin biopsy, since this enables us to do both biochemical and molecular testing. Once the individual mutation is identified, testing for parental mosaicism or sibling status can be done with a blood test. Please note that no specimen will be accepted without prior authorization and consent form. A consent form can be obtained by request only. See contact information below.

Who is Eligible: The BEMB offers both biochemical and molecular OI testing for children with types II, III, or IV OI who are participants in NICHD Clinical Program for OI, their parents and siblings and selected additional individuals of any age with more unusual genetic situations. In almost all cases, we first clinically examine the individual to be tested. Funds for travel to the NIH are available for most pediatric cases.

How to contact us:Please forward requests or questions via email to oiprogram@mail.nih.gov or the BEMB clinical phone line at 301-496-0741. When leaving a message please be sure to include your full name with spelling and the best contact number so that we may return your call promptly.